An Open Label Study to Assess the Efficacy, Safety, Tolerability and Pharmacokinetics of a Single Dose of MMV390048 in Adult Patients With Acute, Uncomplicated Plasmodium Vivax or Falciparum Malaria Monoinfection Over a 35 Day Period
Overview
- Phase
- Phase 2
- Intervention
- MMV390048
- Conditions
- Malaria
- Sponsor
- Medicines for Malaria Venture
- Enrollment
- 8
- Locations
- 2
- Primary Endpoint
- Number of Participants With Crude Adequate Clinical and Parasitological Response (ACPR) for P. Vivax
- Status
- Terminated
- Last Updated
- 4 years ago
Overview
Brief Summary
The present proof-of-concept Phase IIa study aims to confirm, in patients, the observed activity of MMV390048 against P. falciparum in pre-clinical models and the human Induced Blood-Stage Malaria (IBSM) challenge model, and to determine the activity against P. vivax malaria in patients, both over 14 and 28 days. Additional aims are to characterise the safety of MMV390048 in patients. Patient safety will be monitored for up to 35 days post-dose including pharmacokinetic assessments. The study will investigate descending single doses of MMV390048 in response to results obtained in the first cohort/dose in each malaria sub-type. The results of this trial will identify active, well-tolerated doses for investigation in combination with a partner drug within a Phase IIb clinical trial.
Detailed Description
The present Phase IIa study aims to confirm, in patients, the observed activity of MMV390048 against P. falciparum in pre-clinical models and the human IBSM human challenge model, and to determine the activity against P. vivax malaria in patients, both over 14 and 28 days. Additional aims are to characterise the safety of MMV390048 in patients. Patient safety will be monitored for up to 35 days post-dose including pharmacokinetic assessments. The study will investigate descending single doses of MMV390048 in response to results obtained in the first cohort/dose in each malaria sub type. The results of this trial will identify active, well tolerated doses for investigation in combination with a partner drug within a Phase IIb clinical trial. Preclinical studies using SCID mice inoculated with P. falciparum-infected red blood cells link doses and exposures to the efficacy of MMV390048.38 The active dose in the SCID model causing maximum effect (ED90) against the parasites is 1 mg/kg/day. The MPC derived from the SCID data was 39 ng/ml.39 A human dose for the treatment of P. falciparum was sought that could maintain blood concentrations above 39 ng/ml (100 nM) for 8 days. Assuming linear pharmacokinetics and based on observed data from the Phase I exploratory formulation study in human volunteers, a dose of approximately 20 mg would be estimated to achieve the pharmacodynamic target drug concentration in humans based on the preclinical efficacy data generated in the SCID mice model. For new antimalarial drugs the translation of a predicted efficacious dose from the SCID mouse to the human challenge model and in turn to the treatment of acute, uncomplicated P. vivax or P. falciparum is unknown. To minimise the risk to patients and to ensure the highest probability of success, the maximum safe dose (as determined in healthy volunteers) that maintains a toxicokinetic safety margin to the repeat dose studies was selected for the first cohort in this study. This dose is expected to exceed the predicted MPC on Day 8 and provide significant target coverage at the site of action.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Body weight between 40 kg and 90 kg inclusive
- •Presence of P. vivax or P. falciparum monoinfection confirmed by:
- •Fever, as defined by axillary temperature ≥37.5°C or oral/rectal/tympanic temperature ≥38°C, or history of fever in the previous 48 hours for P. vivax and 24 hours for P. falciparum and,
- •Microscopically confirmed parasite infection: 1,000 to 40,000 asexual parasite count/µL blood
- •Written informed consent provided by the patient in accordance with local practice. If the patient is unable to write, witnessed consent is permitted according to local ethical considerations.
- •Ability to swallow oral medication
- •The patient is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is likely to complete the study as planned
- •Willing to be hospitalized for at least 72 hours or until malarial parasites are not detected by microscopy on 2 consecutive occasions whichever comes later and return to clinic for all follow-up visits
- •Women must be of non-childbearing potential (WNCBP) as per one of the following definitions:
- •postmenopausal defined as having age-appropriate, natural (spontaneous) amenorrhea for at least 12 months prior to screening in the absence of an alternative medical cause for the amenorrhea, or
Exclusion Criteria
- •Patients with signs and symptoms of severe / complicated malaria according to the World Health Organisation Criteria 2012
- •Mixed Plasmodium infection
- •Vomiting more than three times in the 24 hours prior to inclusion in the study or inability to tolerate oral treatment, or diarrhea equivalent to three or more watery stools per day
- •Women who are nursing (lactating)
- •Presence of other serious or chronic clinical condition requiring hospitalisation
- •Severe malnutrition (defined as a body mass index \[BMI\] of less than 16 kg/m2 as per local guidelines)
- •Presence of concurrent febrile illness (e.g. typhoid fever)
- •Known history or evidence of clinically significant:
- •cardiovascular disease (including arrhythmia, QTcF interval \>450 msec, personal or family history of long QT syndrome, PR interval \>200msec; any relevant intra-ventricular heart block \[QRS \>120msec\]),
- •respiratory conditions (including active tuberculosis),
Arms & Interventions
Cohort 1A - P. vivax malaria
A single oral dose of up to 120mg MMV390048
Intervention: MMV390048
Cohort 1B - P. falciparum malaria
A single oral dose of up to 120mg MMV390048
Intervention: MMV390048
Cohort 2A - P. vivax malaria
A single oral dose (to be determined) of MMV390048
Intervention: MMV390048
Cohort 2B - P. falciparum malaria
A single oral dose (to be determined) of MMV390048
Intervention: MMV390048
Cohort 3A - P. vivax malaria
A single oral dose (to be determined) of MMV390048
Intervention: MMV390048
Cohort 3B - P. falciparum malaria
A single oral dose (to be determined) of MMV390048
Intervention: MMV390048
Outcomes
Primary Outcomes
Number of Participants With Crude Adequate Clinical and Parasitological Response (ACPR) for P. Vivax
Time Frame: On Day 14 post-dose
The absence of parasitaemia (thick smear) on Day 14, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure. Parasitaemia was defined as a P. vivax asexual forms count \>0
For P. Falciparum: PCR-adjusted Crude Adequate Clinical and Parasitological Response (ACPR)
Time Frame: On Day 14 post-dose
Number of participants meeting PCR-adjusted Crude Adequate Clinical and Parasitological Response (ACPR)